GRHPR – Primary Hyperoxaluria Type 2

GRHPR encodes glyoxylate reductase/hydroxypyruvate reductase; biallelic variants cause Primary Hyperoxaluria Type 2, an autosomal recessive disorder leading to oxalate and L-glycerate accumulation. Clinically, PH2 presents with recurrent nephrolithiasis (HP:0000787), nephrocalcinosis (HP:0000121), and progressive renal insufficiency (HP:0000083), often culminating in end-stage renal disease. The association was first established by identification of a homozygous c.103del (p.Asp35fs) mutation in four patients from two unrelated families (PMID:10484776). Subsequent studies have expanded the allelic spectrum.

Genetic evidence supports an autosomal recessive inheritance. Over 20 unrelated probands have been reported with biallelic GRHPR variants, including missense and truncating alleles. Key variants include c.934A>G (p.Asn312Asp) (PMID:19296982) and c.454dup (p.Thr152AsnfsTer39) (PMID:28569194). Segregation in two consanguineous pedigrees demonstrated co-segregation of pathogenic alleles with disease in four additional affected relatives.

The variant spectrum encompasses missense (e.g., p.Gly165Asp), nonsense (p.Arg99Ter), frameshift (p.Thr152AsnfsTer39), splice site (c.865+1G>T), and founder alleles across ethnic groups. Recurrent mutations such as c.494G>A (p.Gly165Asp) have been observed in South Asian cohorts, whereas c.103del is frequent in Caucasians.

Functional assays consistently demonstrate loss of GRHPR activity. COS cell expression of missense mutants (p.Gly165Asp, p.Met322Arg) shows negligible enzymatic function (PMID:11030416). The p.Asn312Asp variant abolishes activity in site-directed mutagenesis, and molecular modeling reveals disrupted substrate binding domain folding (PMID:19296982). Combined liver-kidney transplantation cases further implicate hepatic predominance of GRHPR function.

No studies have refuted the association. Reports linking GRHPR mutations to atypical hemolytic uremic syndrome highlight mechanistic interplay but do not dispute PH2 pathogenesis. Currently, therapeutic RNAi approaches show efficacy in PH1 but not in PH2, underscoring the need for PH2-specific strategies.

In conclusion, the GRHPR–PH2 association is definitive, with robust genetic and functional concordance. Early genetic testing is critical for diagnosis, prognostication, family counseling, and guiding transplantation decisions. Key take-home: GRHPR mutation screening should be performed in patients with recurrent nephrolithiasis and nephrocalcinosis, particularly in consanguineous settings.

References

• Human molecular genetics • 1999 • The gene encoding hydroxypyruvate reductase (GRHPR) is mutated in patients with primary hyperoxaluria type II. PMID:10484776
• Human genetics • 2000 • Identification of missense, nonsense, and deletion mutations in the GRHPR gene in patients with primary hyperoxaluria type II (PH2). PMID:11030416
• The Journal of urology • 2009 • Late diagnosis of primary hyperoxaluria type 2 in the adult: effect of a novel mutation in GRHPR gene on enzymatic activity and molecular modeling. PMID:19296982
• BMC medical genetics • 2017 • Severe child form of primary hyperoxaluria type 2 - a case report revealing consequence of GRHPR deficiency on metabolism. PMID:28569194
• Kidney international • 2019 • Patients with primary hyperoxaluria type 2 have significant morbidity and require careful follow-up. PMID:31685312

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